Compounds that act at the benzodiazepine (BZ) site of the 3-aminobutyric acid type-A (GABAA) receptor have profound effects on memory. For example, there is accumulating evidence that BZ-site inverse agonists, which attenuate GABA's action at the receptor, can act as cognitive enhancing agents. In particular, compounds with selectivity for 15 subunit-containing GABAA receptors appear to have cognition-enhancing effects without the unwanted side effects associated with non-selective compounds. Our proposal will focus on 15GABAA receptors as a target site for developing cognitive enhancing agents for treating Alzheimer's disease. A key rationale for this approach is that GABA neurons in the temporal cortex and associated areas are largely preserved in patients with Alzheimer's disease, and these preserved neurons contain 15GABAA receptors. In order to identify compounds for mechanistic studies, a drug discovery approach will be used in which targeted experiments in mice advance new compounds for evaluation in monkey cognition tasks. In two specific aims, we will evaluate the following hypotheses: (1) Based on a pharmacophore model of GABAA receptors, we predict that increasing activity at specific determinants of the 15GABAA receptor binding pocket (L2), as well as creation of bivalent ligands based on these compounds, will result in behaviorally-active, 15GABAA receptor-selective ligands; and (2) we predict that inverse agonist action at 15GABAA receptors will enhance performance in cognitive tasks in monkeys and transgenic (APPSwe Tg2576) mice. This translational approach should provide important information for identifying lead compounds for development as cognitive enhancing agents for Alzheimer's disease and other cognitive disorders. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is a chronic, progressive, and ultimately fatal neurodegenerative disease, and there currently are few broadly effective treatment options. The overall goal of this application is to explore the potential for new compounds, acting at a brain protein called the GABA receptor, to enhance cognitive function. Because these compounds appear to be remarkably safe, they may provide a promising new approach for treating memory decline associated with Alzheimer's and other related disorders.